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1.
Nat Commun ; 12(1): 2590, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972513

RESUMO

Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI95% [-8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI95% [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Progressão da Doença , Fibrinolíticos/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo
2.
Nat Commun ; 12(1): 2897, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006844

RESUMO

Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 16/genética , Neurônios Dopaminérgicos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Rede Nervosa/metabolismo , Transmissão Sináptica/genética , Proteína rhoA de Ligação ao GTP/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Variações do Número de Cópias de DNA , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/fisiologia , Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Rede Nervosa/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transmissão Sináptica/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/metabolismo
3.
Nat Commun ; 12(1): 1068, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594066

RESUMO

A graphdiyne-based artificial synapse (GAS), exhibiting intrinsic short-term plasticity, has been proposed to mimic biological signal transmission behavior. The impulse response of the GAS has been reduced to several millivolts with competitive femtowatt-level consumption, exceeding the biological level by orders of magnitude. Most importantly, the GAS is capable of parallelly processing signals transmitted from multiple pre-neurons and therefore realizing dynamic logic and spatiotemporal rules. It is also found that the GAS is thermally stable (at 353 K) and environmentally stable (in a relative humidity up to 35%). Our artificial efferent nerve, connecting the GAS with artificial muscles, has been demonstrated to complete the information integration of pre-neurons and the information output of motor neurons, which is advantageous for coalescing multiple sensory feedbacks and reacting to events. Our synaptic element has potential applications in bioinspired peripheral nervous systems of soft electronics, neurorobotics, and biohybrid systems of brain-computer interfaces.


Assuntos
Grafite/farmacologia , Neurônios Eferentes/fisiologia , Sinapses/fisiologia , Dendritos/efeitos dos fármacos , Dendritos/fisiologia , Teoria da Densidade Funcional , Difusão , Íons , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Plasticidade Neuronal , Neurônios Eferentes/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Temperatura
4.
Nat Neurosci ; 24(3): 326-330, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33603228

RESUMO

By investigating the topology of neuronal co-activity, we found that mnemonic information spans multiple operational axes in the mouse hippocampus network. High-activity principal cells form the core of each memory along a first axis, segregating spatial contexts and novelty. Low-activity cells join co-activity motifs across behavioral events and enable their crosstalk along two other axes. This reveals an organizational principle for continuous integration and interaction of hippocampal memories.


Assuntos
Condicionamento Operante/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Sacarose/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Condicionamento Operante/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Rede Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos
5.
Psychopharmacology (Berl) ; 238(4): 1157-1169, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33483802

RESUMO

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/uso terapêutico , Sistema Límbico/efeitos dos fármacos , Adolescente , Adulto , Idoso , Antidepressivos/administração & dosagem , Clonidina/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/psicologia , Feminino , Giro do Cíngulo/efeitos dos fármacos , Alucinógenos/efeitos adversos , Humanos , Infusões Intravenosas , Ketamina/administração & dosagem , Ketamina/antagonistas & inibidores , Sistema Límbico/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Simpatolíticos/uso terapêutico , Resultado do Tratamento , Adulto Jovem
6.
Br J Anaesth ; 126(4): 835-844, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33386125

RESUMO

BACKGROUND: Propofol, a commonly used intravenous anaesthetic, binds to type A gamma aminobutyric acid (GABA) receptors in mammalian brain. Previous work on its anaesthetic action has characterised either the biochemistry underlying propofol binding or the associated changes in brain network dynamics during sedation. Despite these advances, no study has focused on understanding how propofol action at the cellular level results in changes in brain network connectivity. METHODS: We used human whole-brain microarray data to generate distribution maps for genes that mark the primary GABAergic cortical interneurone subtypes (somatostatin, parvalbumin [PV], and 5-hydroxytryptamine 3A. Next, 25 healthy participants underwent propofol-induced sedation during resting state functional MRI scanning. We used partial least squares analysis to identify the brain regions in which connectivity patterns were most impacted by propofol sedation. We then correlated these multimodal cortical patterns to determine if a specific interneurone subtype was disproportionately expressed in brain regions in which connectivity patterns were altered during sedation. RESULTS: Brain networks that were significantly altered by propofol sedation had a high density of PV-expressing GABAergic interneurones. Brain networks that anticorrelated during normal wakefulness, namely the default mode network and attentional and frontoparietal control networks, increased in correlation during sedation. CONCLUSIONS: PV-expressing interneurones are highly expressed in brain regions with altered connectivity profiles during propofol-induced sedation. This study also demonstrates the utility of leveraging multiple datasets to address multiscale neurobiological problems.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Interneurônios/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Parvalbuminas , Propofol/farmacologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Interneurônios/metabolismo , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Parvalbuminas/metabolismo , Análise Serial de Proteínas/métodos
7.
J Neurosci ; 41(5): 901-910, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472824

RESUMO

Post-traumatic stress disorder (PTSD) is characterized by hypervigilance, increased reactivity to unpredictable versus predictable threat signals, deficits in fear extinction, and an inability to discriminate between threat and safety. First-line pharmacotherapies for psychiatric disorders have limited therapeutic efficacy in PTSD. However, recent studies have advanced our understanding of the roles of several limbic neuropeptides in the regulation of defensive behaviors and in the neural processes that are disrupted in PTSD. For example, preclinical studies have shown that blockers of tachykinin pathways, such as the Tac2 pathway, attenuate fear memory consolidation in mice and thus might have unique potential as early post-trauma interventions to prevent PTSD development. Targeting this pathway might also be beneficial in regulating other symptoms of PTSD, including trauma-induced aggressive behavior. In addition, preclinical and clinical studies have shown the important role of angiotensin receptors in fear extinction and the promise of using angiotensin II receptor blockade to reduce PTSD symptom severity. Additional preclinical studies have demonstrated that the oxytocin receptors foster accurate fear discrimination by facilitating fear responses to predictable versus unpredictable threats. Complementary human imaging studies demonstrate unique neural targets of intranasal oxytocin and compare its efficacy with well-established anxiolytic treatments. Finally, promising data from human subjects have demonstrated that a selective vasopressin 1A receptor antagonist reduces anxiety induced by unpredictable threats. This review highlights these novel promising targets for the treatment of unique core elements of PTSD pathophysiology.


Assuntos
Ansiedade/metabolismo , Emoções/fisiologia , Sistema Límbico/metabolismo , Neuropeptídeos/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Emoções/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Humanos , Sistema Límbico/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Neuropeptídeos/farmacologia , Neuropeptídeos/uso terapêutico , Receptores de Taquicininas/antagonistas & inibidores , Receptores de Taquicininas/metabolismo , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Taquicininas/antagonistas & inibidores , Taquicininas/metabolismo
8.
Neuroimage ; 227: 117633, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33316393

RESUMO

We present a detailed analysis of the Hindriks and van Putten thalamocortical mean-field model for propofol anesthesia [NeuroImage 60(23), 2012]. The Hindriks and van Putten (HvP) model predicts increases in delta and alpha power for moderate (up to 130%) prolongation of GABAA inhibitory response, corresponding to light anesthetic sedation. Our analysis reveals that, for deeper anesthetic effect, the model exhibits an unexpected abrupt jump in cortical activity from a low-firing state to an extremely high-firing stable state (∼250 spikes/s), and remains locked there even at GABAA prolongations as high as 300% which would be expected to induce full comatose suppression of all firing activity. We demonstrate that this unphysiological behavior can be completely suppressed with appropriate tuning of the parameters controlling the sigmoidal functions that map soma voltage to firing rate for the excitatory and inhibitory neural populations, coupled with elimination of the putative population-dependent anesthetic efficacies introduced in the HvP model. The modifications reported here constrain the anesthetized brain activity into a biologically plausible range in which the cortex now has access to a moderate-firing state ("awake") and a low-firing ("anesthetized") state such that the brain can transition from "awake" to "anesthetized" states at a critical level of drug concentration. The modified HvP model predicts a drug-effect hysteresis in which the drug concentration required for induction is larger than that at emergence. In addition, the revised model shows a decrease in the intensity and frequency of alpha-band fluctuations, transitioning to delta-band dominance, with deepening anesthesia. These predicted drug concentration-dependent changes in EEG dynamics are consistent with clinical reports.


Assuntos
Anestésicos Intravenosos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Modelos Neurológicos , Rede Nervosa/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Propofol/farmacologia , Córtex Cerebral/fisiologia , Humanos , Rede Nervosa/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia
9.
Neuroimage ; 227: 117668, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359350

RESUMO

The neuropeptide oxytocin is a key modulator of social-emotional behavior and its intranasal administration can influence the functional connectivity of brain networks involved in the control of attention, emotion and reward reported in humans. However, no studies have systematically investigated the effects of oxytocin on dynamic or directional aspects of functional connectivity. The present study employed a novel computational framework to investigate these latter aspects in 15 oxytocin-sensitive regions using data from randomized placebo-controlled between-subject resting state functional MRI studies incorporating 200 healthy subjects. In order to characterize the temporal dynamics, the 'temporal state' was defined as a temporal segment of the whole functional MRI signal which exhibited a similar functional interaction pattern among brain regions of interest. Results showed that while no significant effects of oxytocin were found on brain temporal state related characteristics (including temporal state switching frequency, probability of transitions between neighboring states, and averaged dwell time on each state) oxytocin extensively (n = 54 links) modulated effective connectivity among the 15 regions. The effects of oxytocin were primarily characterized by increased effective connectivity both between and within emotion, reward, salience, attention and social cognition processing networks and their interactions with the default mode network. Top-down control over emotional processing regions such as the amygdala was particularly affected. Oxytocin also increased effective homotopic interhemispheric connectivity in almost all these regions. Additionally, the effects of oxytocin on effective connectivity were sex-dependent, being more extensive in males. Overall, these findings suggest that modulatory effects of oxytocin on both within- and between-network interactions may underlie its functional influence on social-emotional behaviors, although in a sex-dependent manner. These findings may be of particular relevance to potential therapeutic use of oxytocin in psychiatric disorders associated with social dysfunction, such as autism spectrum disorder and schizophrenia, where directionality of treatment effects on causal interactions between networks may be of key importance .


Assuntos
Encéfalo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Ocitocina/farmacologia , Adulto , Mapeamento Encefálico/métodos , Método Duplo-Cego , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Adulto Jovem
10.
Neuroimage ; 227: 117653, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33338615

RESUMO

Investigating changes in brain function induced by mind-altering substances such as LSD is a powerful method for interrogating and understanding how mind interfaces with brain, by connecting novel psychological phenomena with their neurobiological correlates. LSD is known to increase measures of brain complexity, potentially reflecting a neurobiological correlate of the especially rich phenomenological content of psychedelic-induced experiences. Yet although the subjective stream of consciousness is a constant ebb and flow, no studies to date have investigated how LSD influences the dynamics of functional connectivity in the human brain. Focusing on the two fundamental network properties of integration and segregation, here we combined graph theory and dynamic functional connectivity from resting-state functional MRI to examine time-resolved effects of LSD on brain networks properties and subjective experiences. Our main finding is that the effects of LSD on brain function and subjective experience are non-uniform in time: LSD makes globally segregated sub-states of dynamic functional connectivity more complex, and weakens the relationship between functional and anatomical connectivity. On a regional level, LSD reduces functional connectivity of the anterior medial prefrontal cortex, specifically during states of high segregation. Time-specific effects were correlated with different aspects of subjective experiences; in particular, ego dissolution was predicted by increased small-world organisation during a state of high global integration. These results reveal a more nuanced, temporally-specific picture of altered brain connectivity and complexity under psychedelics than has previously been reported.


Assuntos
Encéfalo/efeitos dos fármacos , Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Rede Nervosa/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Mapeamento Encefálico/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino
11.
J Clin Neurosci ; 84: 82-90, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33358344

RESUMO

AIM: There is rapidly increasing evidence that remission of MDD is associated with substantial changes in functional brain connectivity. These New data have provided a holistic view on the mechanism of antidepressants on multiple levels that goes beyond their conventional effects on neurotransmitters. METHOD: The study was approved by the Local Ethics Committee of Istanbul Medipol University (10840098-604.01.01-E.65129) and followed the Helsinki Declaration principles. In our study, we have evaluated the effect of six weeks of treatment with antidepressants (escitalopram and duloxetine), and tested the underlying brain functional connectivity through a Graph analysis approach in a well-defined first-episode, drug-naive, and non-comorbid population with MDD. RESULTS: Beyond indicating that there was a significant correlation between the antidepressant response and topological characteristics of the brain, our results suggested that global rather than regional network alterations may be implicated in the antidepressant effect. CONCLUSION: Despite the small-sample size and non-controlled study design, our study provides important and relevant clinical data regarding the underlying mechanisms of the antidepressants on topological dynamics in the human brain.


Assuntos
Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Rede Nervosa/efeitos dos fármacos , Adulto , Encéfalo/fisiopatologia , Citalopram/uso terapêutico , Estudos Transversais , Cloridrato de Duloxetina/farmacologia , Cloridrato de Duloxetina/uso terapêutico , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Rede Nervosa/fisiopatologia
12.
Am J Physiol Endocrinol Metab ; 320(3): E467-E474, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356996

RESUMO

The arcuate nucleus (ARC) of the hypothalamus comprises two antagonistic neuron populations critical for energy balance, namely, the anorexigenic pro-opiomelanocortin (POMC) and the orexigenic agouti-related peptide (AgRP) neurons that act as agonists and antagonists, respectively, for neurons expressing the type IV melanocortin receptor (MC4R) (Andermann ML and Lowell BB. Neuron 95: 757-778, 2017). MC4R activation increases energy expenditure and decreases food intake during positive energy balance states to prevent diet-induced obesity (DIO). Work from our group identified aberrant neuronal cell cycle events both as a novel biomarker and druggable target in the ARC for the treatment of DIO, demonstrating pharmacological restoration of retinoblastoma protein function in the ARC using cyclin-dependent kinase 4/6 (CDK4/6) inhibitors could treat DIO in mice by increasing lipid oxidation to selectively decrease fat mass. However, the role of CDK4/6 inhibitors on food intake was not examined. Four-week-old Mc4r-loxTB mice were continuously administered high-fat diet (60% kcal fat). At 8 wk of age, animals were administered 60 mg/kg abemaciclib orally or a saline control and monitored every 2 wk for fat mass changes by MRI. At 11 wk of age, all animals were injected bilaterally in the paraventricular hypothalamus with AAV8 serotype virus expressing a Cre-mCherry and monitored for another 5 wk. Restoration of Mc4r expression in the paraventricular hypothalamic nucleus (PVN/PVH) reduced food intake in hyperphagic obese mice when given CDK4/6 inhibitor therapy. The reduced food intake was responsible for reduced fat mass in mice treated with abemaciclib. These results indicate that targeting POMC neurons could be an effective strategy in treating diet-related obesity.NEW & NOTEWORTHY We have defined some of the necessary components to prevent high-fat diet-induced obesity at the molecular and cellular level. Within POMC neurons, the retinoblastoma protein must remain active and prevented from phosphoinactivation by cyclin-dependent kinases. The downstream neurons within the PVH must also properly express MC4R for the circuit to appropriately regulate feeding behavior.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Melanocortinas/metabolismo , Rede Nervosa/efeitos dos fármacos , Obesidade/tratamento farmacológico , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 4 de Melanocortina/genética , Transdução de Sinais/efeitos dos fármacos
13.
J Neurosci ; 41(6): 1274-1287, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33380470

RESUMO

Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore, in vivo calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.SIGNIFICANCE STATEMENT Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases in vivo neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer's disease.


Assuntos
Microglia/metabolismo , Rede Nervosa/metabolismo , Estimulação Luminosa/métodos , Córtex Visual/metabolismo , Aminopiridinas/farmacologia , Animais , Feminino , Masculino , Camundongos , Microglia/química , Microglia/efeitos dos fármacos , Rede Nervosa/química , Rede Nervosa/efeitos dos fármacos , Pirróis/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Córtex Visual/química , Córtex Visual/efeitos dos fármacos
14.
Anesthesiology ; 133(4): 774-786, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930729

RESUMO

BACKGROUND: It is a commonly held view that information flow between widely separated regions of the cerebral cortex is a necessary component in the generation of wakefulness (also termed "connected" consciousness). This study therefore hypothesized that loss of wakefulness caused by propofol anesthesia should be associated with loss of information flow, as estimated by the effective connectivity in the scalp electroencephalogram (EEG) signal. METHODS: Effective connectivity during anesthesia was quantified by applying bivariate Granger to multichannel EEG data recorded from 16 adult subjects undergoing a slow induction of, and emergence from, anesthesia with intravenous propofol. During wakefulness they were conducting various auditory and motor tasks. Functional connectivity using EEG coherence was also estimated. RESULTS: There was an abrupt, substantial, and global decrease in effective connectivity around the point of loss of responsiveness. Recovery of behavioral responsiveness was associated with a comparable recovery in information flow pattern (expressed as normalized values). The median (interquartile range) change was greatest in the delta frequency band: decreasing from 0.15 (0.21) 2 min before loss of behavioral response, to 0.06 (0.04) 2 min after loss of behavioral response (P < 0.001). Regional decreases in information flow were maximal in a posteromedial direction from lateral frontal and prefrontal regions (0.82 [0.24] 2 min before loss of responsiveness, decreasing to 0.17 [0.05] 2 min after), and least for information flow from posterior channels. The widespread decrease in bivariate Granger causality reflects loss of cortical coordination. The relationship between functional connectivity (coherence) and effective connectivity (Granger causality) was inconsistent. CONCLUSIONS: Propofol-induced unresponsiveness is marked by a global decrease in information flow, greatest from the lateral frontal and prefrontal brain regions in a posterior and medial direction. Loss of information flow may be a useful measure of connected consciousness.


Assuntos
Anestésicos Intravenosos/administração & dosagem , Córtex Cerebral/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Propofol/administração & dosagem , Inconsciência/induzido quimicamente , Adulto , Córtex Cerebral/fisiologia , Eletroencefalografia/métodos , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Masculino , Rede Nervosa/fisiologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Inconsciência/psicologia
15.
Proc Natl Acad Sci U S A ; 117(32): 19556-19565, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694207

RESUMO

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.


Assuntos
Encéfalo/fisiopatologia , Dependência de Morfina/fisiopatologia , Rede Nervosa/fisiopatologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Conectoma , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Morfina/administração & dosagem , Morfina/efeitos adversos , Dependência de Morfina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia
16.
Proc Natl Acad Sci U S A ; 117(20): 11118-11125, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32358198

RESUMO

Cortical network functioning critically depends on finely tuned interactions to afford neuronal activity propagation over long distances while avoiding runaway excitation. This importance is highlighted by the pathological consequences and impaired performance resulting from aberrant network excitability in psychiatric and neurological diseases, such as epilepsy. Theory and experiment suggest that the control of activity propagation by network interactions can be adequately described by a branching process. This hypothesis is partially supported by strong evidence for balanced spatiotemporal dynamics observed in the cerebral cortex; however, evidence of a causal relationship between network interactions and cortex activity, as predicted by a branching process, is missing in humans. Here this cause-effect relationship is tested by monitoring cortex activity under systematic pharmacological reduction of cortical network interactions with antiepileptic drugs. This study reports that cortical activity cascades, presented by the propagating patterns of epileptic spikes, as well as temporal correlations decline precisely as predicted for a branching process. The results provide a missing link to the branching process theory of cortical network function with implications for understanding the foundations of cortical excitability and its monitoring in conditions like epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Eletrocorticografia , Epilepsia , Humanos , Redes Neurais de Computação , Neurônios/fisiologia
17.
Proc Natl Acad Sci U S A ; 117(21): 11788-11798, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32393630

RESUMO

Down syndrome (DS) is the most common form of intellectual disability. The cognitive alterations in DS are thought to depend on brain regions critical for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Neuroimaging studies suggest that increased brain connectivity correlates with lower intelligence quotients (IQ) in individuals with DS; however, its contribution to cognitive impairment is unresolved. We recorded neural activity in the PFC and HPC of the trisomic Ts65Dn mouse model of DS during quiet wakefulness, natural sleep, and the performance of a memory test. During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal-hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing. During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal-hippocampal functional connectivity. Memory performance and key neurophysiological alterations were rescued after 1 month of chronic administration of a green tea extract containing epigallocatequin-3-gallate (EGCG), which improves executive function in young adults with DS and Ts65Dn mice. Our findings suggest that abnormal prefrontal-hippocampal circuit dynamics are candidate neural mechanisms for memory impairment in DS.


Assuntos
Síndrome de Down/fisiopatologia , Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , Reconhecimento Psicológico/fisiologia , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Modelos Animais de Doenças , Função Executiva/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Fármacos Neuroprotetores/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos
18.
Psychopharmacology (Berl) ; 237(6): 1873-1883, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32307560

RESUMO

BACKGROUND: The thalamus is a major target of dopaminergic projections and is densely connected with the prefrontal cortex. A better understanding of how dopamine changes thalamo-cortical communication may shed light on how dopamine supports cognitive function. Methylphenidate has been shown to facilitate cognitive processing and reduce connectivity between the thalamus and lateral prefrontal cortex. AIMS: The thalamus is a heterogeneous structure, and the present study sought to clarify how the intrinsic connections of thalamic sub-regions are differentially impacted by acute dopamine transporter blockade. METHODS: Sixty healthy volunteers were orally administered either 20 mg of methylphenidate (N = 29) or placebo (N = 31) in a double-blind, randomized, between-subject design. Multi-echo fMRI was used to assess intrinsic functional connectivity of sub-regions of the thalamus during a resting state scan. An N-back working-memory paradigm provided a measure of cognitive performance. RESULTS: Acute methylphenidate significantly reduced connectivity of the lateral prefrontal cortex with the motor and somatosensory sub-regions of the thalamus and reduced connectivity with the parietal and visual sub-regions at a trend level. Connectivity with the premotor, prefrontal, and temporal sub-regions was not impacted. The intrinsic connectivity between the thalamus and the lateral prefrontal cortex was not associated with working-memory performance. CONCLUSIONS: Methylphenidate decreases functional connections between the lateral prefrontal cortex and thalamus broadly, while sparing intrinsic connectivity with thalamic sub-regions involved with working-memory and language related processes. Collectively, our results suggest that the dopamine transporter regulates functional connections between the prefrontal cortex and non-cognitive areas of the thalamus.


Assuntos
Imageamento por Ressonância Magnética/métodos , Memória de Curto Prazo/efeitos dos fármacos , Metilfenidato/administração & dosagem , Rede Nervosa/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Adulto , Inibidores da Captação de Dopamina/administração & dosagem , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Tálamo/diagnóstico por imagem , Tálamo/fisiologia , Adulto Jovem
19.
Anesthesiology ; 133(1): 133-144, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32282426

RESUMO

BACKGROUND: A comprehensive understanding of how anesthetics facilitate a reversible collapse of system-wide neuronal function requires measurement of neuronal activity with single-cell resolution. Multineuron recording was performed in Caenorhabditis elegans to measure neuronal activity at varying depths of anesthesia. The authors hypothesized that anesthesia is characterized by dyssynchrony between neurons resulting in a collapse of organized system states. METHODS: Using light-sheet microscopy and transgenic expression of the calcium-sensitive fluorophore GCaMP6s, a majority of neurons (n = 120) in the C. elegans head were simultaneously imaged in vivo and neuronal activity was measured. Neural activity and system-wide dynamics were compared in 10 animals, progressively dosed at 0%, 4%, and 8% isoflurane. System-wide neuronal activity was analyzed using principal component analysis. RESULTS: Unanesthetized animals display distinct global neuronal states that are reflected in a high degree of correlation (R = 0.196 ± 0.070) between neurons and low-frequency, large-amplitude neuronal dynamics. At 4% isoflurane, the average correlation between neurons is significantly diminished (R = 0.026 ± 0.010; P < 0.0001 vs. unanesthetized) and neuron dynamics shift toward higher frequencies but with smaller dynamic range. At 8% isoflurane, interneuronal correlations indicate that neuronal activity remains uncoordinated (R = 0.053 ± 0.029; P < 0.0001 vs. unanesthetized) with high-frequency dynamics that are even further restricted. Principal component analysis of unanesthetized neuronal activity reveals distinct structure corresponding to known behavioral states. At 4% and 8% isoflurane this structure is lost and replaced with randomized dynamics, as quantified by the percentage of total ensemble variance captured by the first three principal components. In unanesthetized worms, this captured variance is high (88.9 ± 5.4%), reflecting a highly organized system, falling significantly at 4% and 8% isoflurane (57.9 ± 11.2%, P < 0.0001 vs. unanesthetized, and 76.0 ± 7.9%, P < 0.001 vs. unanesthetized, respectively) and corresponding to increased randomization and collapse of system-wide organization. CONCLUSIONS: Anesthesia with isoflurane in C. elegans corresponds to high-frequency randomization of individual neuron activity, loss of coordination between neurons, and a collapse of system-wide functional organization.


Assuntos
Anestesia por Inalação , Anestésicos Inalatórios/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Isoflurano/farmacologia , Rede Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Corantes Fluorescentes , Interneurônios/efeitos dos fármacos , Rede Nervosa/diagnóstico por imagem , Análise de Componente Principal , Sevoflurano/farmacologia
20.
Nat Commun ; 11(1): 1466, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193428

RESUMO

The positive or negative value (valence) of past experiences is normally integrated into neuronal circuits that encode episodic memories and plays an important role in guiding behavior. Here, we show, using mouse behavioral models, that glutamatergic afferents from the ventral tegmental area to the dorsal hippocampus (VTA→DH) signal negative valence to memory circuits, leading to the formation of fear-inducing context memories and to context-specific reinstatement of fear. To a lesser extent, these projections also contributed to opioid-induced place preference, suggesting a role in signaling positive valence as well, and thus a lack of dedicated polarity. Manipulations of VTA terminal activity were more effective in females and paralleled by sex differences in glutamatergic signaling. By prioritizing retrieval of negative and positive over neutral memories, the VTA→DH circuit can facilitate the selection of adaptive behaviors when current and past experiences are valence congruent.


Assuntos
Hipocampo/fisiologia , Memória/fisiologia , Rede Nervosa/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Condicionamento Clássico , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiologia , Medo/fisiologia , Feminino , Inativação Gênica/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Glutamatos/metabolismo , Hipocampo/efeitos dos fármacos , Cinética , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Rede Nervosa/efeitos dos fármacos , Optogenética , Receptores de N-Metil-D-Aspartato/metabolismo , Caracteres Sexuais , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/efeitos dos fármacos , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
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